The long-term objectives of our research are to elucidate gene by environment interactions that contribute to HDL cholesterol (HDL-C) and other cardiovascular disease risk factors. The HDL-C-raising effects of estrogen therapy (ET) are well-documented, yet recent trials showed a lack of expected cardioprotective effects among women taking ET. The current proposal explores the possibility that genetic variation in the HDL receptor, SR-BI, may underlie HDL-C response to ET. SR-BI also exhibits a paradoxical relationship: overexpression results in lower levels of HDL-C, yet is atheroprotective. SR-BI is known to be regulated by estrogen and several studies support associations between SR-BI polymorphisms and HDL-C levels that appear to be sex-specific, which may indicate a modifying role of estrogen on the gene variants. Preliminary analysis of a two-locus SR-BI haplotype among postmenopausal women from the Rancho Bernardo Study has revealed a significant gene-by-ET interaction affecting HDL-C levels. Our analysis suggests that the underlying variant(s) responsible for the observed association have yet to be found. Our hypothesis is that there are one or more underlying genetic variants of SR-BI which influence HDL-C levels in an estrogen-dependent manner. The specific aims of this proposal are:1.) to survey genetic variation in SR-BI coding and regulatory regions; 2.) to examine associations between these SR-BI variants and HDL-C among postmenopausal women; 3.) to determine if the genetic effects are modified by use of ET; and 4.) explore whether these variants are also associated with HDL-C in men. Approximately 700 of each postmenopausal women and men from the Rancho Bernardo Study, a large population-based cohort collected prior to the widespread use of lipid lowering therapies, will be evaluated. We will carry out linkage disequilibrium mapping of common and rare SR-BI polymorphisms identified through public SNP databases and through re-sequencing of evolutionarily-conserved gene regions and putative estrogen response and other regulatory elements. This project will contribute to the understanding of how estrogen therapy influences lipid levels, and may elucidate a mechanism to explain why users of estrogen therapy are not protected from heart disease despite having favorable HDL-C levels. This may result in future clinically useful diagnostic tests that aid postmenopausal women in their decision whether to use estrogen therapy.